15-Deoxy-16-hydroxy-16-methyl-Δ19-prostaglandins of the E and F series

ABSTRACT

The inventions disclosed herein relates to pharmacologically active Δ19 prostaglandins of the E and F series in which C-16 is substituted with hydroxyl and methyl as well as the pharmacologically acceptable, non toxic lower alkyl esters and salts thereof, and to the intermediates and processes for producing such compounds.

BACKGROUND OF THE INVENTION

(1) Field of the Invention

The present invention relates to 15-deoxy-16-hydroxy-16-methyl-Δ¹⁹-prostaglandins, as well as the pharmaceutically acceptable, non-toxiclower alkyl esters and salts thereof, and to the intermediates andprocesses for producing such compounds.

(2) Description of the Prior Art

Prostaglandins have classically been described as chemically related 20carbon chain hydroxy fatty acids having the basic skeleton of prostanoicacid: ##STR1##

The prostaglandins having a hydroxyl group at the C-11 position and aketo group at the C-9 position are known as the PGE series, and thosehaving a hydroxyl group in place of the keto group are known as the PGFseries and are further designated by an α or β suffix to indicate theconfiguration of the hydroxyl group at said position. The naturalcompounds are the α-hydroxy substituted compounds. They may containdifferent degrees of unsaturation in the molecule, particularly at C-5,C-13 and C-17, the unsaturation is also indicated by a suffix. Thus, forexample, the PGF₁ and PGE₁ series refer to prostanoic acids having atrans olefin bond at the C-13 position, while the PGF₂ and PGE₂ seriesrefer to prostadienoic acids having a cis-olefin bond at the C-5position and a trans olefin bond at the C-13 position. For a review onprostaglandins and the definition of primary prostaglandins, see, forexample, P. Ramwell, The Prostaglandins, 1, pp. 5-22 (1973).

The preparation of derivatives of prostanoic acid has become of greatimportance since the demonstration of the highly interesting range ofbiological and pharmacological activities of natural prostaglandins.

The great majority of these studies have focused on modification of thetwo side chains, or modifications of the substituents attached to thecyclopentane moiety [see for example U. Axen et al., Synthesis Vol. 1,John Wiley and Sons Inc., New York, New York. 1973 and P. H. Bently,Chem. Soc. Reviews, 2, 29 (1973)].

The synthesis of prostaglandin analogs possessing a 3-oxa- or11-deoxy-3-thia moiety have been described, among others in U.S. Pat.No. 3,873,607; U.S. Pat. No. 3,950,406; Netherlands Patent No.7305222-Q; U.S. Pat. No. 3,944,593; U.S. Pat. 3,931,289; and U.S. Pat.No. 3,936,487.

The synthesis of several prostaglandin analogs wherein the hydroxylgroup at C-15 has been removed and a hydroxyl group has been introducedat C-16 has appeared [see for example, U.S. Pat. No. 3,950,406;Prostaglandins, Vol. 10, 733 (1975); Tetrahedron Letters, No. 48, 4217(1975)].

Recently, reports have also appeared wherein the C-16 carbon bearing ahydroxyl group is substituted with a methyl group [see Pappo et al.,Tetrahedron Letters, No. 4, 235 (1975); Collin et al., U.S. Pat. No.3,965,143; and Belgium Patent No. 827,127].

Also, a patent has recently appeared wherein the C-16 carbon bearing thehydroxyl group is substituted with vinyl, methylvinyl, and cyclopropyl(U.S. Pat. 4,061,670).

Introduction of unsaturation at C-19-C-20 has been reported in the15-hydroxy series in U.S. Pat. 4,064,351. However, the C-20 carbon wasmono- or di-substituted.

In addition, 19-methyl-Δ18-PGF₂ α was reported by Dr. Vorbruggen at theSalford Symposium or Prostanoids, July, 1978.

SUMMARY OF THE PRESENT INVENTION

In accordance with the present invention, we have prepared certain novel15-deoxy-16-hydroxy-16-methyl-Δ19-prostaglandin analogs represented bythe following formula: ##STR2## wherein Y is ##STR3## R₁ is selectedfrom the group consisting of hydrogen and hydroxyl; R₂ is selected fromthe group consisting of hydrogen and C₁ -C₆ alkyl;

Z is selected from the group consisting of a divalent moiety of theformulae: --(CH₂)_(n) --, --(CH₂)_(m) OCH₂ --, --(CH₂)_(m) SCH₂ --,##STR4## wherein n is 5 to 7, preferably 6, m is 3 to 5, preferably 4,and p is 2 to 7, preferably 3; the racemic mixture thereof; and when R₁is hydrogen, the pharmacologically acceptable salts thereof.

The dotted lines shown in the above formula and in the formulas belowindicate that the substituents are in configuration, i.e., below theplane of the cyclopentane ring.

The double bond at C-13 in the compounds of the present invention hasthe same configuration as in natural prostaglandins of the PGE and PGFseries, that is the trans configuration.

The symbol Δ¹⁹ used herein the specifications represents a double bondbetween C₁₉ -C₂₀.

These novel compounds possess asymmetric centers and thus can beproduced as racemic mixtures or as individual enantiomers. The racemicmixtures can be resolved if desired at appropriate stages by methodsknown to those skilled in the art, to obtain the respective individualenantiomers. It is to be understood that the racemic mixtures and theindividual 8R-enantiomers are encompassed within the scope of thepresent invention.

When the compounds of the present invention are racemic mixtures, theyare produced starting from racemates, while when the compounds of theinvention are individual enantiomers the compounds are preferablyobtained starting from the appropriate individual enantiomer.

Useful pharmacologically acceptable salts of the above formula, where R₁is hydrogen, are those with pharmacologically acceptable metal cations,ammonium, amine cations or quaternary ammonium cations.

Preferred metal cations are those derived from the alkali metals, e.g.,lithium, sodium and potassium, and from the alkaline earth metals, e.g.,magnesium and calcium, although cationic forms of other metals, e.g.aluminum, zinc and iron, are within the scope of this invention.

Pharmacologically acceptable amine cations are those derived fromprimary, secondary or tertiary amines such as mono-, di- ortrimethylamine, ethylamine, dibutylamine, triisopropylamine,N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine,cyclopentylamine, dicyclohexylamine, mono- or dibenzylamine, α- orβ-phenyethylamine, ethylenediamine, and arylipatic amines containing upto and including 18 carbon atoms, as well as heterocyclic amines, e.g.,piperidine, morpholine, pyrrolidine, piperazine and lower alkylderivatives thereof, e.g. 1-methylpiperidine, 4-ethylmorpholine,1-isopropylpyrrolidine, 2-methylpyrrolidine, 1,4-dimethylpiperazine,2-methylpiperidine, and the like, as well as amines containingwater-solubilizing or hydrophilic groups, e.g. mono-, di-, ortriethanolamine, ethyldiethanolamine, N-butylethanolamine,2-amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol,2-amino-2-methyl-1-propanol, tris-(hydroxymethyl)-aminomethane,N-phenylethanolamine, N-(p-tert-amylphenyl)-diethanolamine, galactamine,N-methylglucamine, N-methylglucosamine, ephedrine, phenylephrine,epinephrine, procaine, and the like.

Examples of suitable pharmacologically acceptable quaternary ammoniumcations are tetramethylammonium, tetraethylammonium,benzyltrimethylammonium, phenyltriethylammonium and the like.

The novel compounds of this invention can be prepared by a1,4-conjugate-addition procedure involving treatment of the etherblocked cyclopentenone (11) with a lithio-cuprate reagent such as (8),(9) or (10) prepared as illustrated in Flowsheets A and B.

Although Flowsheets A and B exemplify the use of a trimethylsilylhydroxyl protecting group, any protecting group which survives theconjugate addition reaction described by these tables and the examplesof this application may be employed. Suitable protecting groupstherefore include tri-(C₁ -C₄)-alkylsilyl, or other acid labileprotecting groups such as tetrahydropyranyl, tetrahydrofuranyl, or otheracetals, Moreover, with reference to the lithio cuprates of Flowsheet B(structures 8, 9 or 10) in addition to the lithiocuprates described, theintermediates of structures (14) and (15) may also be employed. ##STR5##

In accordance with the procedure outlined in Flowsheet A, treatment ofthe ketone (1) with propargylmagnesium bromide (2) provides thehydroxyalkyne (3) which is silylated to give the ether (4). The TMSether (4) is heated with tri-n-butylstannane in the presence ofazobisisobutyronitrile (AIBN) to afford the trans vinylstannane (5)which contains 10% to 20% of the corresponding cis vinylstannane (6).

Treatment of the vinylstannyl reagents (5,6) with n-butyl lithium attemperatures of -78° C. to -10° C. generates the vinyl lithium reagents(7). ##STR6##

In accordance with Flowsheet B for the preparation of the asymmetricallithio-cuprate (8), a solution of one molar equivalent of copper(I)-1-alkyne, preferably copper (I)-1-pentyne in anhydroustributylphosphine or HMPTA, preferably one to five molar equivalents, inether is added to one molar equivalent of the aforementioned vinyllithium solution cooled to about -78° C. After about one hour at thistemperature, a molar equivalent of the requisite cyclopentenone (11) isadded. After several hours at -30° C. to -70° C. the reaction mixture isquenched with aqueous ammonium chloride solution and the blocked product(12) is isolated in the usual manner.

It is also possible to effect conjugate 1,4-addition with theasymmetrical lithio-cuprate (10) from vinyl lithium and cuprousthiophenoxide. A solution of vinyl lithium (7) in ether at -78° C. isreacted with an equimolar amount of a reagent prepared by admixture, inether at a temperature of 0° C. to -78° C., of equimolar amounts ofcuprous thiophenoxide and copper (I) iodide tributlyphosphonium complex.After about 30 minutes at this temperature, the lithio-cuprate istreated with the requisite cyclopentenone (11) as described hereinabovefor the conjugate addition with 1-alkynyl lithio-cuprate (8).

For the preparation of the symmetrical lithio-cuprate (9), one molarequivalent of copper (I) iodide tributylphosphine complex, dissolved inanyhydrous ether, is added at about -78° C. to two molar equivalents ofthe aforementioned vinyl lithium (7) solution cooled to -78° C. Afterabout one hour at this temperature, the lithio-cuprate (9) is treatedwith the requisite cyclopentenone (11) as described hereinabove for theconjugate addition with the 1-alkynyl lithio-cuprate (8).

The procedures for conjugate addition involving organocopper reagentsare well known in the art, see for example C. J. Sih, et al., J. Amer.Chem. Soc., 97, 865 (1975), which is incorporated by reference.

In the cases where R'₁ =trimethylsilyloxy in cyclopentenone (11) theconjugate addition is performed at -78° C. to -40° C. The reaction isquenched by addition of an ether solution of acetic acid. Removal ofblocking groups is then carried out as described in the reference aboveto provide the product (13) wherein R₁ and R₂ are as hereinabove.

The introduction of a racemic β-chain possessing the16-hydroxy-16-methyl-Δ¹⁹ moieties provides a pair of prostaglandinsepimeric at C-16. These two epimers may be separated into their upper(less polar) and lower (more polar) components by high-pressure liquidchromatography (HPLC) or by dry-column or preparative thin layersilica-gel chromatography.

If an optically active protected cyclopentenone such as (11) isutilized, then HPLC separation will provide the corresponding opticallyactive nat. 9-oxo-11α, 16α-dihydroxy-16-methyl-Δ¹⁹ and nat. 9-oxo-11α,16β-dihydroxy-16-methyl-Δ¹⁹ -PGE enantiomers.

All available evidence leads us to believe that the ##STR7##

function introduced by the cuprate process occupies a position trans tothe 11-oxy function. Similarly, we are led to the conclusion that in theproduct (13) the two side-chains attached to C₈ and C₁₂ are trans toeach other. However, we are not certain of this configurationalrelationship in the product as it is obtained directly from the cuprateprocess. These products may have the side-chains in a trans- orcis-relationship or they may be a mixture containing both the trans- andcis-isomers. This is indicated in the nomenclature of the compoundsinvolved by the designation 8ξ. In order to ensure a trans-relationshipin (13) these products can be submitted to conditions known in theliterature to equilibrate the cis-8-iso-PGE₁ to a mixture containingabout 90% of the trans product. These conditions involve treatment withpotassium acetate in aqueous methanol for 96 hours at room temperature.

The triloweralkylsilyloxy substituted lithio-cuprate reagents of type(7) and the trialkylstannyl precursors are novel and useful compoundswhich are also embraced by this invention. They may be defined bygeneric formulae (14) and (15). ##STR8## wherein W is R-Sn wherein R istri-(C₁ -C₆)-alkyl and preferably a tri-n-butyl group, or W is lithium;R₈ is tri-C₁,-C₄ alkylsilyl, preferably trimethylsilyl or other acidlabile protecting groups such as tetrahydropyranyl, tetrahydrofuranyl orother acetals; R₉ is thiophenoxide, substituted thiophenoxide whereinthe substituent may be C₁ -C₄ alkyl, C₁ -C₄ alkoxy, C₁ -C₃ dialkylaminoor phenyl, or R₉ may be C₃ -C₄ alkyne or the identical vinyl moiety.

The cyclopentenones required for the preparation of the E₁, E₂, 3-oxa,and 11-deoxy-3-thia series have been described in the literature. Thecyclopentenone for the preparation of 3-thia-11-hydroxy prostaglandinsis described in Flowsheet C.

In accordance with Flowsheet C which is hereinbelow described, treatmentof 2-furyl lithium (16) with a ω-chloroaldehyde (17) provides thechloroalcohol (18). Treatment of the chloroalcohol (18) withethylmercaptoacetate furnishes the hydroxyester (19) which uponhydrolysis with sodium formate/formic acid provides the3-hydroxy-cyclopentenone (20). Treatment of the cyclopentenone (20) withsulfuric acid provides the required 4-hydroxy-cyclopentenone (21) whichafter treatment with chlorotrimethylsilane provides the bissilylatedcyclopentenone (22). ##STR9##

In accordance with Flowsheet D, when the 11-hydroxy or 11-oxyderivatives are treated with dilute acid, it is possible to effectelimination and the formation of the corresponding Δ¹⁰ derivatives (23)of the prostaglandin A-type. A preferred procedure involves treatment intetrahydrofuran:water (2:1) solvent 0.5 N in HCl for about 30 hours atambient temperature. Under these conditions a tetrahydropyranyl ortrialkylsilyl ester or ether will undergo hydrolysis. ##STR10##

The prostaglandin carboxylic acids of this invention can be readilyconverted to the various alkyl esters of this invention by treatment inthe usual manner with the appropriate diazoalkane. The preparation ofdiazoalkanes by various procedures are well described in the art. Seefor example, C. D. Gutsche, Organic Reactions, VIII, 389 (1954). Certainof the esters of this invention can also be obtained directly by use ofthe appropriate cyclopentenone ester. The various esters can also beprepared by any of several procedures well-known in the art via an acidchloride (prior blocking of free alcohol groups with appropriateblocking groups such as trialkylsilyl, tetrahydropyranyl and the like)or mixed anhydrides and treatment of these intermediates with theappropriate alcohol. Mixed anhydrides can be obtained by treatment ofthe prostaglandin acid in a solvent such as dioxane at the temperaturein the range of 0° C. to 15° C. with a molar equivalent of atri-alkylamine, preferably triethylamine, tributylamine and the like,and then a molar equivalent of isobutyl chlorocarbonate or the like. Theresulting mixed anhydrides are then treated with the appropriate alcoholto give the derivatized product. [For a pertinent literature analogy seeProstaglandins, 4, 768 (1973).]

An alternative procedure involves treatment of the prostaglandin acidwith a molar equivalent of the trialkyl amine in an excess of theappropriate alcohol in an anhydrous solvent such as methylene chloride,molar equivalent of p-toluenesulfonyl chloride is then added (ifnecessary, a second molar equivalent can be added) and after stirring atambient temperatures for about 15 minutes to one hour the product isworked-up in the usual manner. (For a pertinent literature analogy, seeU.S. Pat. No. 3,821,279.) A third procedure involves the use ofdicyclohexylcarbodiimide in the usual manner; for a pertinent literatureanalogy see German Offen. No. 2,365,205; Chem. Abst., 81, 120098 g(1974).

The esterified alcohol derivatives of this invention are also preparedin the usual manner by procedures well known in the art from theappropriate alkanoic acid anhydride or acid chloride.

When the compounds of this invention are prepared from racemic startingcompounds, two racemates are obtained. In appropriate instances theseracemates may be separated from each other by careful application of theusual chromatographic procedures. In the more difficult instances it maybe necessary to apply high pressure liquid chromatography includingrecycling techniques. [See G. Fallick, American Laboratory, 19-27(August 1973) as well as references cited therein. Additionalinformation, concerning high speed liquid chromatography and theinstruments necessary for its application, is available from WatersAssociate Inc., Maple Street, Milford, Mass.]. ##STR11##

In accordance with Flowsheet E treatment of a prostaglandin of the Eseries (9-oxo)(13) with a carbonyl reducing reagent such as sodiumborohydride provides a mixture of the corresponding PGFα (9β-hydroxy)(24) and PGFβ (9β-hydroxy(25) analogs. These two epimeric alcohols arereadily separated by silica gel chromatography.

If one utilized the individual 16α-hydroxy or 16β-hydroxy E startingmaterial, after separating the 9β product by silica gel chromatography,the isolated products are the 9α,16α-dihydroxy and 9α,16β-dihydroxyderivatives, respectively.

Use of a stereoselective reagent such aslithiumperhydro-9b-boraphenalylhydride [H. C. Brown and W. C. Dickason,J.A.C.S., 92, 709 (1970)] or lithium tri-secbutylborohydride [H. C.Brown and S. Krishnamurthy, Ibid, 94, 7159 (1972)] provides the PGFproduct (24) as the selective species.

Likewise, utilization of either the individual 16α- or 16β-hydroxy Ecompounds affords the corresponding 9α,16α-dihydroxy and9α,16β-dihydroxy prostaglandins of this invention respectively.##STR12## Wherein Z' is ##STR13## wherein n, m and p are as previouslydefined.

In accordance with Flowsheet F, when 11α-hydroxy-PGF2α congeners such as(24) are treated with an oxidizing reagent such as Jones Reagent, orpyridinium chlorochromate, a selective oxidation is provided to give thecorresponding PGD derivative (9α-hydroxy-11-keto)(26) which is isolatedafter chromatographic purification.

If one utilizes the individual 16α-hydroxy or 16β-hydroxy PGFαderivative of (24), then the corresponding 9α,16α dihydroxy-11-oxo and9α,16β-dihydroxy-11-oxo-prostaglandins are isolated, respectively.

In the following formulae Z is as hereinabove defined.

The 4-hydroxycyclopentenone racemates may be resolved into theircomponent enantiomers (28) and (29) wherein Z is as hereinabove definedby derivatizing the ketone function with a reagent having an opticallyactive center. The resulting diastereoisomeric mixture can then beseparated by fractional crystallization, or by chromatography, or byhigh speed liquid chromatography involving, if necessary, recyclingtechniques. Among the useful optically active ketone derivatizingreagents are 1-α-aminoxy-β-methylpentanoic acid hydrochloride (to give(27)), (R)-2-aminoxy-3,3-dimethylbutyric acid hydrochloride, and4-α-methylbenzyl semicarbazide. After separation of the diastereomericderivatives, reconstitution of the keto function provides the individual4-hyroxycyclopentenone enantiomers (28) and (29). A useful procedure forthe resolution of a 4-hydroxycyclopentenone racemate via an oxime suchas (27) is described in the art [R. Pappo, P. Collins and C. Jung,Tetrahedron Letters, 943 (1973)]. The resolution of thehydroxycyclopentenone (28) herein Z is ##STR14## is described by Bruhnet al, Tetrahedron Letters, 235 (1976). ##STR15##

The novel compounds of the present invention have potential utility ashypotensive agents, anti-ulcer agents, agents for the treatment ofgastric hypersecretion and gastric erosion, agents to provide protectionagainst the ulcerogenic and other gastric difficulties associated withthe use of various nonsteroidal anti-inflammatory agents (e.g.,indomethacin, aspirin, and phenylbutazone), bronchodilators,anti-inflammatory agents, abortifacients, agents for the induction oflabor, agents for the induction of menses, fertility-controlling agents,oestrus regulators for use in animal husbandry with cattle and otherdomestic animals and central nervous system regulatory agents. Certainof the novel compounds of this invention possess utility asintermediates for the preparation of the other novel compounds of thisinvention.

The novel compounds of this invention possess the pharmacologicalactivity described below as associated with the appropriateabove-described prostaglandin types.

The known PGE, PGF.sub.α, PGF.sub.β, PGA and PGD compounds are allpotent in causing multiple biological responses even at low doses. Forexample, PGE₁, PGE₂, PGA₁ and PGA₂ are extremely potent in causingvasodepression and smooth muscle stimulation, and also are potent asantilipolytic agents. For example, the 11-deoxy-PGE compounds of thisinvention are selective in that they are at most relatively weakstimulants of smooth muscle. A further advantage of these novelcompounds should be in their increased stabilities and lengthenedself-lives.

Therefore, each of these novel prostaglandin analogs of this inventionshould be more useful than one of the corresponding above-mentionedknown prostaglandins for at least one of the pharmacological purposesindicated below for the latter, either because it has a different andnarrower spectrum of biological activity than the known prostaglandins,and therefore is more specific in its activity and causes smaller andfewer undesired side effects than the known prostaglandins, or becauseof its prolonged activity, fewer and smaller doses of the novelprostaglandin analog can frequently be used to attain the desiredresult.

Another advantage of the novel compounds of this invention, comparedwith the known prostaglandins, is that these novel compounds areadministered effectively orally, sublingually, intravaginally, buccally,or rectally, in addition to the usual intravenous, instramuscular, orsubcutaneous injection or infusion methods indicated above for the usesof the known prostaglandins. These qualities are advantageous becausethey facilitate maintaining uniform levels of these compounds in thebody with fewer, shorter, or smaller doses, and make possibleself-administration by the patient.

PGE₁, PGE₂, PGE₃, dihydro-PGE₁, PGF.sub.α, PGF.sub.β and PGA compounds,their esters and pharmacologically acceptable salts, are extremelypotent in causing various biological responses. For that reason, thesecompounds are useful for pharmacological purposes. See, for example,Bergstrome, et al., Pharmacol. Rev., 20, 1 (1968), and references citedherein. A few of those biological responses are systemic arterial bloodpressure lowering in the case of the PGA and PGE compounds as measured,for example, in anesthetized (sodium phenobarbital) pentolinium-treatedrats with indwelling aortic and right heart cannulas; pressor activity,similarly measured, for the PGF compounds; stimulation of smooth muscleas shown, for example, by tests on strips of guinea pig ileum, rabbitduodenum, or gerbil colon; potentiation of other smooth musclestimulants; antilipolytic activity as shown by antagonism ofepinephrine-induced mobilization of free fatty acids or inhibition ofthe spontaneous release of glycerol from isolated rat fat pads;inhibition of gastric secretion in the case of PGE compounds, as shownin dogs with secretion stimulated by food or histamine infusion;activity on the central nervous system; decrease of blood plateletadhesiveness in the case of PGE, as shown by platelet-to-glassadhesiveness, and inhibition of blood platelet aggregation and thrombusformation induced by various physical stimuli, e.g., arterial injury,and various biochemical stimuli, e.g., ADP, ATP, serotonin, thrombin,and collagen, and in the case of the PGE and PGA compounds, stimulationof epidermal proliferation and keratinization, as shown when they areapplied in culture to embryonic chick and rat skin segments.

Because of these biological responses, these known prostaglandins areuseful to study, prevent, control, or alleviate a wide variety ofdisease and undesirable physiological conditions in birds and mammalsincluding humans, useful domestic animals, pets, and zoologicalspecimens, and in laboratory animals, e.g., mice, rats, rabbits, andmonkeys.

For example, these compounds are useful in mammals, including man, asnasal decongestants. For this purpose, the compounds are used in a doserange of about 0.01 mg to about 10 mg per ml of a pharmacologicallysuitable liquid vehicle or as an aerosol spray, both for topicalapplication.

PGA, PGF.sub.β and PGE compounds are useful as hypotensive agents toreduce blood pressure in mammals including man. For this purpose, thePGF.sub.β compounds are administered by intravenous infusion at the rateof about 0.01 mg to about 40 mg per Kg of body weight per minute, or ina single dosage or multiple doses of about 25 mg to 2500 mg per Kg ofbody weight total per day. The PGE and PGA compounds are administered byintravenous infusion at the rate of about 0.01 to about 50 mg per Kg ofbody weight per minute, or in a single dose or multiple doses of about25 to 2500 mg per Kg of body weight total per day.

The PGE, PGF.sub.α and PGF.sub.β compounds are useful in place ofoxytocin to induce labor in pregnant female animals, including humans,cows, sheep and pigs, at or near term or in pregnant animals withintrauterine death of the fetus from about 20 weeks to term. For thispurpose, the PGF compound is infused intravenously at a dose of 0.01 mgto 50 mg per Kg of body weight per minute until or near the terminationof the second stage of labor, i.e., expulsion of the fetus. Similarly,the PGE compound is infused intravenously at a dose of 0.01 to 50 mg perKg of body weight per minute until or near the expulsion of the fetus.These compounds are especially useful when the female is one or moreweeks postmature and natural labor has not started, or 12 to 60 hoursafter the membranes have ruptured and natural labor has not yet started.

The PGE, PGF.sub.α and PFG.sub.β compounds are useful for controllingthe reproductive cycle in ovulating female mammals, including humans andother animals. For that purpose, PGF₂α, for example, is administeredsystemically at a dose level in the range of 0.01 mg to about 20 mg perKg of body weight, advantageously during a span of time startingapproximately at the time of ovulation and ending approximately at thetime of menses or just prior to menses. Likewise, a PGE compound isadministered in the same fashion at a dose level of 0.01 mg to about 50mg per Kg of body weight. Additionally, expulsion of an embryo or fetusis accomplished by similar administration of the compound during thefirst third or the second third of the normal mammalian gestationperiod. Accordingly, such compounds are useful as abortifacients. Theyare also useful for induction of menses during approximately the firsttwo weeks of a missed menstrual period and thus, are useful ascontraceptive anti-fertility agents.

11α-hydroxy-PGE compounds are extremely potent in causing stimulation ofsmooth muscle, and are also highly active in potentiating other knownsmooth muscle stimulators, for example, oxytocic agents, e.g., oxytocin,and the various ergot alkaloids including derivatives and analogsthereof. Therefore PGE₂, for example, is useful in place of or incombination with less than usual amounts of these known smooth musclestimulators for example, to relieve the symptoms of paralytic ileus, tocontrol or prevent uterine bleeding after abortion or delivery, to aidin expulsion of the placenta, and during the puerperium. For the latterpurpose, the PGE compound is administered by intravenous infusionimmediately after abortion or delivery at a dose in the range about 0.01to about 50 mg per Kg of body weight per minute until the desired effectis obtained. Subsequent doses are given by intravenous, subcutaneous, orintramuscular injection or infusion during puerperium in the range of0.01 to 2 mg er Kg of body weight per day, the exact dose depending onthe age, weight, and condition of the patient or animal.

The novel PGA, PGE and PGF.sub.β of this invention are also useful asbronchodilators for the treatment of asthma and chronic bronchitis. Assuch they may be conveniently administered by inhalation of aerosolsprays prepared in a dose range of about 10 μg to about 10 mg/ml of apharmacologically suitable liquid vehicle. Relative to the naturalprostaglandins, the PGA and PGE compounds in particular have thesignificant advantage of inducing prolonged effects.

The PGE and PGA compounds are also useful in mammals, including man andcertain useful animals, e.g., dogs and pigs, to reduce and controlexcessive gastric secretion, thereby reducing or avoiding gastricerosion or gastrointestinal ulcer formation, and accelerating thehealing of such ulcers already present in the gastrointestinal tract.For this purpose, the compounds are injected or infused intravenously,subcutaneously, or intramuscularly in an infusion dose range of about0.1 mg to about 500 mg per Kg of body weight per minute, or in a totaldaily dose by injection or infusion in the range of about 0.1 to about20 mg per Kg of body weight per day, the exact dose depending on theage, weight, and condition of the patient or animal, and on thefrequency and route of administration. These compounds may also beuseful in conjuction with various non-steroidal anti-inflammatoryagents, such as aspirin, phenylbutazone, indomethacin and the like, tominimize the well-known ulcerogenic effects of the latter.

The PGE and PGA compounds also stimulate epidermal proliferation andkeratinization, and in such a capacity are useful to promote andaccelerate healing of skin which has been damaged, for example, byburns, wounds, abrasions or surgery. The action of the PGA compoundsmakes them particularly useful in speeding the adherence and growth ofskin autografts, especially small, deep (Davies) grafts which areintended to cover skinless areas by subsequent outward growth ratherthan initially, and in retarding rejection of homografts.

For these purposes, these compounds are preferably administeredtopically at or near the site where cell growth and keratin formation isdesired, advantageously as an aerosol liquid or micronized powder spray,as an isotonic aqueous solution in the case of wet dressings, or as alotion cream, or ointment in combination with the usual pharmaceuticallyacceptable dilutents. In some instances, when there is substantial fluidloss as in the case of extensive burns or skin loss due to other causes,systemic administration of PGE is advantageous, for example, byintravenous injection or infusion, separate or in combination with theusual infusions of blood, plasma, or substitutes thereof. Alternativeroutes of administration are subcutaneous or intramuscular near thesite, oral, sublingual, buccal, rectal, or vaginal. The exact dosedepends on such factors as the route of administration, and the age,weight, and condition of the subject. Illustrative of a wet dressing fortopical application to second and/or third degree burns of skin area 5to 25 square centimeters is the use of an isotonic aqueous solutioncontaining one to 500 mg/ml of the PGA compound or several times thatconcentration of the PGE compound. Especially for topical use, theseprostaglandins are useful in combination with antibiotics such asgentamycin, neomycin, polymyxin B, bacitracin, spectinomycin, andoxytetracycline; with other antibacterials such as mafenidehydrochloride, sulfadiazine, furazolium chloride, and nitrofurazone; andwith corticoid steroids, such as hydrocortisone, prednisolone,methylprednisolone, and fluoroprednisolone; each of these being used inthe combination at the usual concentration suitable for its use alone.

The PGA compounds and derivatives and salts thereof increase the flow ofblood in the mammalian kidney, thereby increasing the volume andelectrolyte content of the urine. For that reason, PGA compounds areuseful in managing cases of renal disfunction, especially in cases ofseverely impaired renal blood flow, for example, the hepatorena syndromeand early kidney transplant rejection. In case of excessive orinappropriate antidiuretic hormone ADH vasopressin secretion, thediuretic effect of these compounds is even greater. In anephreticstates, the vasopressin action of these compounds is especially useful.

The PGE compounds of this invention are also useful as topicalvasodilators.

The PGE₁ compounds of this invention are useful whenever it is desiredto inhibit platelet aggregation, to reduce the adhesive character ofplatelets, and to remove or prevent the formation of thrombi in mammalsincluding man, rabbits, and rats. For example, these compounds areuseful to treat and prevent myocardial infarcts and post-operativethrombosis. For these purposes, these compounds are administeredsystemically, e.g., intravenously, subcutaneously, intramuscularly, andin the form of sterile implants for prolonged action. For rapidresponse, especially in emergency situations, the intravenous route ofadministration is preferred. Doses in the range of about 0.005 to about20 mg per Kg of body weight per day are used, the exact dose dependingon the age, weight, and condition of the patient or animal, and on thefrequency and route of administration.

It is well known that platelet aggregation inhibitors may be useful asanti-thrombotic drugs. Inhibition of platelet aggregation can beconveniently measured in vitro by monitoring changes in optical densityand/or light transmission in platelet rich plasma upon addition ofsuitable aggregating agents such as adenosine diphosphate, epinephrine,thrombin or collagen. Alternatively, platelet aggregation can bemeasured in vitro using platelet rich plasma obtained at various timeintervals from animals given inhibitors by an oral or parenteral route.

The PGE compounds of the present invention exhibit the ability toinhibit platelet aggregation in vitro when tested by the followingprocedure.

Human protein rich plasma is incubated with modified Tyrode's solutionin a proportion of 40-50% human protein rich plasma. The test compoundsare added at varying concentrations and after 5 minutes incubation, anaggregating agent such as adenosine diphosphate or collagen is added.The change in optical density (light transmission) is monitored by eyeand inhbition is recorded as a (-) or lack of inhibition is recorded asa (+). Test compounds are considered active if they inhibit adenosinediphosphate or collagen induced aggregation at a concentration of 0.025mg/ml or less within 5-10 minutes.

The PGE compounds of this invention also have bronchodilator activity asdetermined in a test using dogs anesthetized, artificially ventilatedand submitted to a continuous respiratory spasm induced by pilocarpine.

Mongrel dogs of either sex weighing between 5 and 10 kg are used. Theyare premedicated with morphine HCl by subcutaneous injection at 1.5mg/Kg. An intravenous perfusion of 5% (W/V) chloralose is started 1/2hour after the morphine injection in such a way that 60 mg/Kg areadministered within 15 minutes. After completion, a continuous perfusionof 10 mg/Kg/hour is maintained throughout the experiment. The dogs areartificially ventilated by means of a Starling pump at a rate of 20breaths/minute. The volume is adjusted according to the weight of theanimal. [Kleinman and Radford, J. Appl. Physiol., 19, 360 (1964)]. Allthe measurements are made with the dogs positioned supine in a heated,V-shaped table. Curarization is obtained by succinylcholine chlorideusing a starting injection of 3 mg/Kg lasting 3 minutes, followed by acontinuous perfusion of 0.1 mg/Kg/minute.

The respiratory spasm is induced by a starting injection of 400 μg/Kg ofpilocarpine HCl lasting 5 minutes. An increase or decrease in the doseof pilocarpine HCl may occur as a function of the observed effect on theairway's resistance. A 15 minute delay is observed before the start of acontinuous perfusion of pilocarpine HCl at a dose of 4 μg/Kg/minute tomaintain a constant spasm during the test.

A metallic cannula is inserted and fixed, after tracheotomy, into theupper part of the trachea. The two cephalic veins and the two femoralveins are catheterized to inject the various agents. The femoral arteryis catheterized to measure the systemic blood pressure. An esophagealballoon (11 cm×2.5 cm) is inserted into the lower third of theoesophagus to measure the endothoracic pressure. The measurement of airflow is made with a Fleish pneumotachograph connected to the trachealtube.

The transpulmonary pressure is measured as follows: The tracheal cannulais equipped with a stainless steel axial tube (1.5 mm) which is closedat its distal end and projected 2.5 cm beyond the end of the cannula.Three holes with a diameter of one mm are pierced on this lattersegment. This tube, which is used to measure the tracheal pressure, isconnected to one of the two chambers of a Sanborn 267 B/C differentialtransducer. The other chamber is connected to the esophageal balloon bymeans of a polyethylene catheter of the same length and characteristicsas the balloon's.

The airflow is measured from the Fleish pneumotachograph by means of aSanborn 270 differential transducer.

The tidal volume is obtained by electronic integration of the flowsignal using an R.C. integrator.

The systemic and pulmonary blood pressures are gauged by means of aSanborn 267 B/C or 1280B pressure transducer.

An electrocardiogram is taken in lead 2. Its use is to monitor a cardiacrate-meter.

All these parameters are recorded on a Sanborn polygraph. Thetranspulmonary pressure and the tidal volume are also displayed asrectangular coordinates on an oscilloscope.

The airway's resistance, expressed in cm of water/liter/second, ismeasured by subtracting from the electrical equivalent of thetranspulmonary pressure, a voltage proportional to the flow so as tosynchronize the pressure and volume signals on the oscilloscope [Meadand Whittenberger, J. Appl. Physiol., 5,779 (1953)].

The value of the pulmonary elastance, expressed in cm of water/liter, isobtained by means of the same principle, i.e., an electrical signalproportioned to the volume is subtracted from the transpulmonarypressure signal, in order to optimize the pressure-flow loop on theoscilloscope.

The details of this method are described by Lulling, et al. [Med.Pharmacol. Exp., 16, 481 (1967)].

The computing operations are carried out with an analogical computerwhich allows the direct reading, cycle to cycle, of the values ofresistance and elastance.

The test compounds are administered by an Aerosol® route. Themicronebulizer of a Bird Mark 7 respirator is fitted on the metalliccannula just after the pneumotachograph. The "puff" of the testcompound, in Aerosol® is driven by a 2 Kg/cm₂ pressure, allowed into themicronebulizer just during one inspiration cycle. The micronebulizer isfitted on the respiratory tube only during the "puff". It is weighedjust before and just after administration to determine the amount oftest compound administered. Approximately 50 mg of the solution isadministered to each dog. In accordance with the Pilocarpine Assaydescribed herein, the compounds of this invention should exhibitbronchodilator activity.

The bronchodilator activity for representative compounds of thisinvention was determined in Guinea-Pigs against bronchospasms elicitedby intravenous injections of serotonin, histamine, and acetylcholine, bythe Konzett procedure the details of which are those discussed by J.Lulling, P Lievens, F. El Sayed and J. Prignot, Arzeimittel-Forschung18, 995 (1968).

In the table which follows, bronchodilator activity for representativecompounds of the invention against spasmogenic agents serotonin,histamine, and acetylcholine is expressed as an ED₅₀ determined from theresults obtained with three logarithmic cumulative intravenous doses.

                  Table A                                                         ______________________________________                                        Konzett Data                                                                              ED.sub.50 mg/kg                                                               Serotonin                                                                             Histamine Acetylcholine                                   ______________________________________                                        dl 9-oxo-11α, 16-                                                                     3.8 × 10.sup.-3                                                                   6.4 × 10.sup.-3                                                                   10.6 × 10.sup.-3                        dihydroxy-                                                                    16-methyl-5-cis,                                                              13-trans-                                                                     19-prostatrienoic acid                                                      ______________________________________                                    

REFERENCE EXAMPLE 1 4-Hydroxy-4-methyl-oct-1-yn-7-ene

A mixture of 19.45 g. of magnesium, 0.15 g. of mercuric chloride and 0.5ml. of 1,2-dibromoethane in 40 ml. of ether, under argon, is stirred for5 minutes. A 0.5 ml. portion of propargylbromide is added followed by160 ml. of ether. To the stirred mixture is added dropwise, a solutionof 60.0 g. of 5-oxo-1-hexene and 87.3 g. of propargyl bromide in 100 ml.of ether, at such a rate as to maintain a vigorous reflux. Afteraddition is complete, the mixture is stirred for 20 minutes, cooled inan ice bath and a saturated solution of ammonium chloride is addeddropwise. The solid is removed by filtration through Celite and washingwith ether. The solvent is removed from the filtrate giving the productas an orange liquid.

REFERENCE EXAMPLE 2 4-Methyl-4-trimethylsilyloxy-oct-1-yn-7-ene

To a mixture of 50 g. of 4-hydroxy-4-methyl-oct-1-yn-7-ene and 61.3 g.of imidazole in 100 ml. of dimethylformamide at 0° C., is added, withstirring, 49.1 g. of trimethylsilyloxy chloride. The mixture is stirredat room temperature overnight and poured into petroleum ether and water.The organic layer is washed with water and saturated sodium bicarbonatesolution and dried over magnesium sulfate. The solvent is removed andthe residue distilled (74°-78° C., 1.5 mm.) to give the product as acolorless liquid.

REFERENCE EXAMPLE 3E-1-Tri-n-butylstannyl-4-methyl-4-trimethylsilyloxy-1,7-octadiene

A mixture of 30 g. of 4-methyl-4-trimethylsilyloxy-oct-1-yn-7-ene, 58.66g. of tri-n-butylstannane and 200 mg. of azobisisobutyronitrile isplaced in a bath at 95° C. and stirred under argon. The mixture isheated at 140° C. for one hour and then at 140° C. under vacuum for 1.5hours. The mixture is distilled via a Kugelrohr at 140° C., 0.06 mm. togive the product as a colorless liquid.

REFERENCE EXAMPLE 411α,16-Dihydroxy-16-methyl-9-oxo-5-cis-13-trans-19-prostatrienoic acid

To a solution of 10.19 g. ofE-1-tri-n-butylstannyl-4-methyl-4-trimethylsilyloxy-1,7-octadiene in 10ml. of tetrahydrofuran at -78° C., under argon, is added with stirring9.3 ml. of 2.2 M. n-butyllithium. The mixture is maintained at -20° to-17° C. for 21/4 hours, then cooled to -78° C. A solution of 2.7 g. ofpentynyl copper and 7.4 g. of tri-n-butyl phosphine in 45 ml. of etheris added. After one hour a solution of 5 g. of4-trimethylsilyloxy-2-(6-carbotrimethylsilyloxy-2-cis-hexenyl)cyclopent-2-en-1-onein 5 ml. of ether is added and the mixture is stirred at -40° C. for 1/2hour, -40° to -20° C. for 1/2 hour and -20° C. for 8 minutes. Thesolution is cooled to -30° C. and 5 ml. of acetic acid followed bysaturated ammonium chloride is added. The mixture is extracted withether and the ether layer is washed with dilute hydrochloric acid. Thesolvent is removed and the residue stirred with 130 ml. of aceticacid:tetrahydrofuran:water (4:2:1) at 40° C. for one hour. The solventsare removed and the residue is dissolved in methanol. The methanolsolution is washed with heptane and the methanol removed. The residue isstirred with a solution of 13 g. of sodium bicarbonate in 150 ml. ofwater for 1/2 hour. A 25 ml. portion of methanol is added, the mixtureis stirred for 15 minutes and extracted with ether. The aqueous layer isacidified first with sodium dihydrogen phosphate and then withhydrochloric acid. This mixture is extracted with ethyl acetate. Theextract is dried over magnesium sulfate and the solvent removed. Theresulting yellow oil is chromatographed on a dry silica gel column,eluting with ether (1% acetic acid) giving the desired product.

REFERENCE EXAMPLE 5 Preparation and Separation of9α,11α,16-Trihydroxy-16-methyl-5-cis,13-trans-19-prostrienoic acid and9β,11α,16-Trihydroxy-16-methyl-5-cis,13-trans-19-prostatrienoic acid

To a stirred, ice-cold solution of9-oxo-11α,16-dihydroxy-16-methyl-5-cis,13-trans-19-prostadienoic acid inethanol is added excess sodium borohydride in small portions during 1minute. The mixture is stirred at 0° C. for 5 minutes and at ambienttemperature for 1.5 hours. The bulk of the ethanol is evaporated invacuo at room temperature and the residue is partitioned with cold, verydilute, hydrochloric acid and ethyl acetate. The organic phase isevaporated and washed with water and brine and dried over magnesiumsulfate and concentrated in vacuo.

The residue is subjected to silica-gel chromatography to give: firsteluted-9α,11α,16-trihydroxy-16-methyl-5-cis,13-trans-19-prostatrienoicacid followed by9β,11α,16-trihydroxy-16-methyl-5-cis,13-trans-19-prostatrienoic acid.

If one starts with the individual 16α or 16β-hydroxy isomer, then thecorresponding products will also be 16α or 16β-hydroxy, respectively.

REFERENCE EXAMPLE 61,9-Dioxo-11α,16-dihydroxy-1-hydroxymethyl-16-methyl-13-trans-19-prostene

To a solution of 5.2 g. ofE-1-tri-n-butylstannyl-4-methyl-4-trimethylsilyloxy-1,7-octadiene in 5ml. of tetrahydrofuran, under argon, is added with stirring, 5.8 ml. of1.8 M. n-butyllithium at -50° C. The solution is maintained at -20° to-10° C. for 2.5 hours and then cooled to -78° C. A solution of 1.37 g.of pentynyl copper and 3.4 g. of tri-n-butyl phosphine in 30 ml. ofether is added. After one hour, 2 g. of4-(1-methoxy-1-methylethoxy)-2-[7-oxo-8-(1-methoxy-1-methylethoxy)octyl]-cyclopent-2-en-1-onein 5 ml. of ether is added. The solution is stirred at -50° C. for 1/2hour then at -30° to -20° C. for 1/2 hour, saturated ammonium chlorideis added and the mixture is extracted with ether. The ether layer iswashed with dilute hydrochloric acid, saturated sodium bicarbonatesolution and saturated ammonium chloride solution. The solvent isremoved and the residue is stirred in 50 ml. of a mixture of aceticacid:tetrahydrofuran:water (4:2:1) for two hours. The solvents areremoved at reduced pressure at 30° C. and the residue is purified byhigh pressure liquid chromatography eluting with ethyl acetate:heptane(4:1) and ethyl acetate. The desired product is recovered in purifiedform.

REFERENCE EXAMPLE 7 PREPARATION OF9α,11α,16-TRIHYDROXY-16-METHYL-5-CIS,13-TRANS-19-PROSTATRIENOIC ACID Toa stirred solution solution of9-oxo-11α,16-dihydroxy-16-methyl-5-cis,13-trans-19-prostadienoic acid intetrahydrofruran (THF) at -78° C. is added an excess of a 0.5 M solutionof lithium perhydro-9β-boraphenalyl hydride in THF. After 30 min. at-78° C., the solution is warmed to 0° C. and treated with water. Thismixture is partitioned with ether-potassium carbonate solutions. Theaqueous phase is carefully acidified with hydrochloric acid, saturatedwith NaCl, and extracted with ethyl acetate. The organic extract iswashed with brine, dried with magnesium sulfate, and concentrated invacuo.

The residue is subjected to silica-gel dry column chromatography toprovide 9α,11α,16-trihydroxy 16-methyl-5-cis,13-trans-19-prostatrienoicacid which may be separated into the individual 16α- and 16β-hydroxylisomers by HPLC techniques.

REFERENCE EXAMPLE 8 PREPARATION OF9-OXO-16-HYDROXY-16-METHYL-5-CIS,10,13-TRANS-Δ¹⁹ -PROSTATETRAENOIC ACID

9-oxo-11α,16-dihydroxy-16-methyl-5-cis,13-trans-Δ¹⁹ -prostatrienoic acidis dissolved in a 1:1 tetrahydrofuran-water mixture containing 0.5 N HCland allowed to stand at ambient temperature under argon for 72 hours.The solution is treated with brine and extracted with ether. The extractis washed with brine, dried over magnesium sulfate, and concentrated invacuo to an oil. This residue is purified by dry column chromatograhy togive 9-oxo-16-hydroxy-16-methyl-5-cis,10,13-trans-Δ¹⁹ -prostatetraenoic.If one utilizes the individual 16α or 16β isomer, the product obtainedis the 16α or 16β- epimer respectively.

REFERENCE EXAMPLE 9 PREPARATION OF9α,16-DIHYDROXY-11-OXO-16-METHYL-5-CIS,13-TRANS-Δ¹⁹ -PROSTATRIENOIC ACID

To a solution of 9α,11α,16-trihydroxy-16-methyl-5-cis,13-trans-Δ¹⁹-prostatrienoic acid in acetone (12 ml/g.) at -35° C. is added, dropwisewith stirring, one equivalent of diluted to 10 ml with water). After 15min isopropanol is added, followed by water. The mixture is poured intowater, saturated with NaCl, extracted with ethyl acetate, dried overmagnesium sulfate, and concentrated in vacuo to an oil.

This oil is chromatographed on a dry column of silica-gel using ethylacetate/heptane mixtures containing 1% acetic acid, to provide theproduct above.

If one starts with either of the individual 16α- or 16β-hydroxylisomers, one isolates the 16α- or 16β-hydroxyl isomer, respectively.

TABLE I

Treatment of the appropriate cyclopentenones of Table B with thelithiocuprates derived from the vinylstannanes or vinyliodides ofReference Example 3 by the procedure of Reference Example 4 isproductive of the PGE₁ derivatives of Examples 1-11 of Table I.

Although in Tables I and II which follow the product listed is thedl-racemic product, when the cyclopentenone employed is an opticallyactive cyclopentenone (such as structure (11)), the application of HPLC,column or thin layer chromatography will provide the individual nat.16α- and nat. 16β compounds.

EXAMPLE 1

VINYL TIN

1-trans-tri-n-EUTYLSTANNYL-4-METHYL-4-TRIMETHYLSILOXY-1,7-OCTADIENE

CYCLOPENTANONE

2-(5-CARBOTRIMETHYLSILOXYPENTYL)-4-TRIMETHYLSILOXYCYCLOPENT-2-EN-1-ONEPRODUCT PROSTAGLANDIN OF THE PGE1 SERIESdl-11α,16-DIHYDROXY-9-OXO-16-METHYL-2-nor-13-trans-Δ¹⁹ PROSTADIENOICACID

EXAMPLE 2

VINYL TIN

1-trans-tri-n-BUTYLSTANNYL-4-METHYL-4-TRIMETHYLSILOXY-1,7-OCTADIENE

CYCLOPENTENONE

2-(6-CARBOTRIMETHYLSILOXYHEXYL)-4-TRIMETHYLSILOXYCYCLOPENT-2-EN-1-ONE

PRODUCT PROSTAGLANDIN OF THE PGE1 SERIES

dl-11α,16-DIHYDROXY-9-OXO-16-METHYL-13-trans-Δ¹⁹ PROSTADIENOIC ACID

EXAMPLE 3

VINYL TIN

1-trans-tri-n-BUTYLSTANNYL-4-METHYL-4-TRIMETHYLSILIOXY-1,7-OCTADIENE

CYCLOPENTENONE

2-(7-CARBOTRIMETHYLSILOXYHEPTYL)-4-TRIMETHYLSILOXYCYCLOPENT-2-EN-1-ONE

PRODUCT PROSTAGLANDIN OF THE PGE1 SERIES

dl-11α,16-DIHYDROXY-9-OXO-16-METHYL-2-homo-13-trans-Δ¹⁹ PROSTADIENOICACID

EXAMPLE 4

VINYL TIN

1-trans-tri-n-BUTYLSTANNYL-4-METHYL-4-TRIMETHYLSILOXY-1,7-OCTADIENE

CYCLOPENTENONE

2-(6-CARBOTRIMETHYLSILOXY-5-THIAHEXYL)-4-TRIMETHYLSILOXYCYCLOPENT-2-EN-1-ON

PRODUCT PROSTAGLANDIN OF THE PGE1 SERIES

dl-11α,16-DIHYDROXY-9-OXO-16-METHYL-3-TIA-13-trans-Δ¹⁹ PROSTADIENOICACID

EXAMPLE 5

VINYL TIN

1-trans-tri-n-BUTYLSTANNYL-4-METHYL-4-TRIMETHYLSILOXY-1,7-OCTADIENE

CYCLOPENTENONE

2-(6-CARBOTRIMETHYLSILOXY-5-OXAHEXYL)-4-TRIMETHYLSILOXYCYCLOPENT-2-EN-1-ONE

PRODUCT PROSTAGLANDIN OF THE PGE1 SERIES

dl-11α,16-DIHYDROXY-9-OXO-16-METHYL-3-OXA-13-trans-Δ¹⁹ -PROSTADIENOICACID

EXAMPLE 6

VINYLL TIN

1-trans-tri-n-BUTYLSTANNYL-4-METHYL-4-TRIMETHYLSILOXY-1,7-OCTADIENE

CYCLOPENTENONE

2-(6-CARBOTRIMETHYLSILOXYHEXYL)-4R-TRIMETHYLSILOXYCYCLOPENT-2-EN-1-ONE

PRODUCT PROSTAGLANDIN OF THE PGE1 SERIES

nat-11α,16-DIHYDROXY-9-OXO-16-METHYL-13-trans-Δ¹⁹ PROSTADIENOIC ACID

EXAMPLE 7

VINYL TIN

1-trans-tri-n-BUTYLSTANNYL-4-METHYL-4-TRIMETHYLSILOXY-1,7-OCTADIENE

CYCLOPENTENONE

2-(5-CARBOETHOXYPENTYL)CYCLOPENT-2-EN-1-ONE

PRODUCT PROSTAGLANDIN OF THE 11-DEOXY PGE1 SERIES

dl-16-HYDROXY-9-OXO-16-METHYL-2-nor-13-trans-Δ¹⁹ PROSTADIENOIC ACID

EXAMPLE 8

VINYL TIN

1-trans-tri-n-BUTYLSTANNYL-4-METHYL-4-TRIMETHYLSILOXY-1,7-OCTADIENE

CYCLOPENTENONE

2-(6-CARBOETHOXYHEXYL)CYCLOPENT-2-EN-1-ONE

PRODUCT PROSTAGLANDIN OF THE 11-DEOXY PGE1 SERIES

dl-16-HYDROXY-9-OXO-16-METHYL-13-trans-Δ¹⁹ PROSTADIENOIC ACID

EXAMPLE 9

VINYL TIN

1-trans-tri-n-PUTYLSTANNYL-4-METHYL-4-TRIMETHYLSILOXY-1,7-OCTADIENE

CYCLOPENTENONE

2-(7-CARBOETHOXYHEPTYL)CYCLOPENT-2-EN-1-ONE

PRODUCT PROSTAGLANDIN OF THE 11-DEOXY PGE1 SERIES

dl-16-HYDROXY-9-OXO-16-METHYL-2-homo-13-trans-Δ¹⁹ PROSTADIENOIC ACID

EXAMPLE 10

VINYL TIN

1-trans-tri-n-BUTYLSTANNYL-4-METHYL-4-TRIMETHYLSILOXY-1,7-OCTADIENE

CYCLOPENTENONE

2-(6-CARBOETHOXY-5-THIAHEXYL)CYCLOPENT-2-EN-1-ONE

PRODUCT PROSTAGLANDIN OF THE 11-DEOXY PGE1 SERIES

dl-16-HYDROXY-9-OXO-16-METHYL-3-THIA-13-trans-Δ¹⁹ PROSTADIENOIC ACID

EXAMPLE 11

VINYL TIN

1-trans-tin-n-PUTYLSTANNYL-4-METHYL-4-TRIMETHYLSILOXY-1,7-OCTADIENE

CYCLOPENTENONE

2-(6-CARBOETHOXY-5-OXAHEXYL)CYCLOPENT-2-EN-1-ONE

PRODUCT PROSTAGLANDIN OF THE 11-DEOXY PGE1 SERIES

dl-16-HYDROXY-9-OXO-16-METHYL-3-OXA-13-trans-Δ¹⁹ PROSTADIENOIC ACID

Treatment of the PGE₁ derivatives of Examples 1-11 of Table I withlithium perhydro-9β-boraphenalyl hydride by the procedure of ReferenceExample 6 is productive of the PGF₁ α derivatives of Examples of TableI.

EXAMPLE 12

STARTING PROSTAGLANDIN OF THE PGE SERIES

dl-11α,16-DIHYDROXY-9-OXO-16-METHYL-2-nor-13-trans-19 PROSTADIENOIC ACID

PRODUCT PROSTAGLANDIN OF THE PGF1α SERIES

dl-9α,11α,16-TRIHYDROXY-16-METHYL-2-nor-13-trans-Δ¹⁹ PROSTADIENOIC ACID

EXAMPLE 13

STARTING PROSTAGLANDIN OF THE PGE SERIES

dl-11α,16-DIHYDROXY-9-OXO-16-METHYL-13-trans-19 PROSTADIENOIC ACID

PRODUCT PROSTAGLANDIN OF THE PGF1α SERIES

dl-9α,11α,16-TRIHYDROXY-16-METHYL-13-trans-Δ¹⁹ PROSTADIENOIC ACID

EXAMPLE 14

STARTING PROSTAGLANDIN OF THE PGE SERIES

dl-11α,16-DIHYDROXY-9-OXO-16-METHYL-2-homo-13-trans-19 PROSTADIENOICACID

PRODUCT PROSTAGLANDIN OF THE PGF1α SERIES

dl-9α,11α,16-TRIHYDROXY-16-METHYL-2-homo-13-trans-Δ¹9 PROSTADIENOIC ACID

EXAMPLE 15

STARTING PROSTAGLANDIN OF THE PGE SERIES

dl-11α,16-DIHYDROXY-9-OXO-16-METHYL-3-THIA-13-trans-19 PROSTADIENOICACID

PRODUCT PROSTAGLANDIN OF THE PGF1α SERIES

dl-9α,11α,16-TRIHYDROXY-16-METHYL-3-THIA-13-trans-Δ¹9 PROSTADIENOIC ACID

EXAMPLE 16

STARTING PROSTAGLANDIN OF THE PGE SERIES

dl-11α,16-DIHYDROXY-9-OXO-16-METHYL-3-OXA-13-trans-19 PROSTADIENOIC ACID

PRODUCT PROSTAGLANDIN OF THE PGF1α SERIES

dl-9α,11α,16-TRIHYDROXY-16-METHYL-3-OXA-13-trans-Δ¹⁹ PROSTADIENOIC ACID

EXAMPLE 17

STARTING PROSTAGLANDIN OF THE PGE SERIES

nat-11α,16-DIHYDROXY-9-OXO-16-METHYL-13-trans-19 PROSTADIENOIC ACID

PRODUCT PROSTAGLANDIN OF THE PGF1α SERIES

nat-9α,11α,16-TRIHYDROXY-16-METHYL-13-trans-Δ¹⁹ PROSTADIENOIC ACID

EXAMPLE 18

STARTING PROSTAGLANDIN OF THE PGE SERIES

dl-16-HYDROXY-9-OXO-16-METHYL-2-nor-13-trans-19 PROSTADIENOIC ACID

PRODUCT PROSTAGLANDIN OF THE 11-DEOXY PGF1α SERIES

dl-9α,16-DIHYDROXY-16-METHYL-2-nor-13-trans-Δ¹⁹ PROSTADIENOIC ACID

EXAMPLE 19

STARTING PROSTAGLANDIN OF THE PGE SERIES

dl-16-HYDROXY-9-OXO-16-METHYL-13-trans-19 PROSTADIENOIC ACID

PRODUCT PROSTAGLANDIN OF THE 11-DEOXY PGF1α SERIES

dl-9α,16-DIHYDROXY-16-METHYL-13-trans-Δ¹⁹ PROSTADIENOIC ACID

EXAMPLE 20

STARTING PROSTAGLANDIN OF THE PGE SERIES

dl-16-HYDROXY-9-OXO-16-METHYL-2-homo-13-trans-19 PROSTADIENOIC ACID

PRODUCT PROSTAGLANDIN OF THE 11-DEOXY PGF1α SERIES

dl-9α,16-DIHYDROXY-16-METHYL-2-homo-13-trans-Δ¹⁹ PROSTADIENOIC ACID

EXAMPLE 21

STARTING PROSTAGLANDIN OF THE PGE SERIES

dl-16-HYDROXY-9-OXO-16-METHYL-3-THIA-13-trans-19 PROSTADIENOIC ACID

PRODUCT PROSTAGLANDIN OF THE 11-DEOXY PGF1α SERIES

dl-9α,16-DIHYDROXY-16-METHYL-3-THIA-13-trans-Δ¹⁹ PROSTADIENOIC ACID

EXAMPLE 22

STARTING PROSTAGLANDIN OF THE PGE SERIES

dl-16-HYDROXY-9-OXO-16-METHYL-3-OXA-13-trans-19 PROSTADIENOIC ACID

PRODUCT PROSTAGLANDIN OF THE 11-DEOXY PGF1α series

dl-9α,16-DIHYDROXY-16-METHYL-3-OXA-13-trans-Δ¹⁹ PROSTADIENOIC ACID

Treatment of the PGE₁ derivatives of Examples 1-7 of Table I with sodiumborohydride by the procedure off Reference Example 15 is productive ofthe PGFα and PFGβ derivatives of Examples 23 to 33 of Table I.

EXAMPLE 23

STARTING PROSTAGLANDIN OF THE PGE SERIES

dl-11α,16-DIHYDROXY-9-OXO-16-METHYL-2-nor-13-trans-19 PROSTADIENOIC ACID

PRODUCT PROSTAGLANDIN OF THE PGF1β SERIES

dl-9β,11α,16-TRIHYDROXY-16-METHYL-2-nor-13-trans-Δ¹⁹ PROSTADIENOIC ACID

EXAMPLE 24

STARTING PROSTAGLANDIN OF THE PGE SERIES

dl-11α,16-DIHYDROXY-9-OXO-16-METHYL-13-trans-19 PROSTADIENOIC ACID

PRODUCT PROSTAGLANDIN OF THE PGF1β SERIES

dl-9β,11α,16-TRIHYDROXY-16-METHYL-13-trans-Δ¹⁹ PROSTADIENOIC ACID

EXAMPLE 25

STARTING PROSTAGLANDIN OF THE PGE SERIES

dl-11α,16-DIHYDROXY-9-OXO-16-METHYL-2-homo-13-trans-19 PROSTADIENOICACID

PRODUCT PROSTAGLANDIN OF THE PGF1β SERIES

dl-9β,11α,16-TRIHYDROXY-16-METHYL-2-homo-13-trans-Δ¹⁹ PROSTADIENOIC ACID

EXAMPLE 26

STARTING PROSTAGLANDIN OF THE PGE SERIES

dl-11α,16-DIHYDROXY-9-OXO-16-METHYL-3-THIA-13-TRANS-19 PROSTADIENOICACID

PRODUCT PROSTAGLANDIN OF THE PGF1β SERIES

dl-9β,11α,16-TRIHYROXY-16-METHYL-3-THIA-13-Trans-Δ¹⁹ PROSTADIENOIC ACID

EXAMPLE 27

STARTING PROSTAGLANDIN OF THE PGE SERIES

dl-11α,16-DIHYDROXY-9-OXO-16-METHYL-3-OXA-13-trans-19 PROSTADIENOIC ACID

PRODUCT PROSTAGLANDIN OF THE PGF1β SERIES

dl-9β,11α,16-TRIHYDROXY-16-METHYL-3-OXA-13-trans-Δ¹⁹ PROSTADNIENOIC ACID

EXAMPLE 28

STARTING PROSTAGLANDIN OF THE PGE SERIES

nat-11α,16-DIHYDROXY-9-OXO-16-METHYL-13-trans-19 PROSTADIENOIC ACID

PRODUCT PROSTAGLANDIN OF THE PGF1β SERIES

nat-6β,11α,16-TRIHYDROXY-16-METHYL-13-trans-Δ¹⁹ PROSTADIENOIC ACID

EXAMPLE 29

STARTING PROSTAGLANDIN OF THE PGE SERIES

dl-16-HYDROXY-9-OXO-16-METHYL-2-nor-13-trans-19 PROSTADIENOIC ACID

PRODUCT PROSTAGLANDIN OF THE 11-DEOXY PGF1β SERIES

dl-9β,16-DIHYDROXY-16-METHYL-2-nor-13-trans-Δ¹⁹ PROSTADIENOIC ACID

EXAMPLE 30

STARTING PROSTAGLANDIN OF THE PGE SERIES

dl-16-HYDROXY-9-OXO-16-METHYL-13-trans-19 PROSTADIENOIC ACID

PRODUCT PROSTAGLANDIN OF THE 11-DEOXY PGF1β SERIES

dl-9β,16-DIHYDROXY-16-METHYL-13-trans-Δ¹⁹ PROSTADIENOIC ACID

EXAMPLE 31

STARTING PROSTAGLANDIN OF THE PGE SERIES

dl-16-HYDROXY-9-OXO-16-METHYL-2-homo-13-trans-19 PROSTADIENOIC ACID

PRODUCT PROSTAGLANDIN OF THE 11-DEOXY PGF1β SERIES

dl-9β,16-DIHYDROXY-16-METHYL-2-homo-13-trans-Δ¹⁹ PROSTADIENOIC ACID

EXAMPLE 32

STARTING PROSTAGLANDIN OF THE PGE SERIES

dl-16-HYDROXY-9-OXO-16-METHYL-3-THIA-13-trans-19 PROSTADIENOIC ACID

PRODUCT PROSTAGLANDIN OF THE 11-DEOXY PGF1β SERIES

dl-9β,16-DIHYDROXY-16-METHYL-3-THIA-13-trans-Δ¹⁹ PROSTADIENOIC ACID

EXAMPLE 33

STARTING PROSTAGLANDIN OF THE PGE SERIES

dl-16-HYDROXY-9-OXO-16-METHYL-3-OXA-13-trans-19 PROSTADIENOIC ACID

PRODUCT PROSTAGLANDIN OF THE 11-DEOXY PGF1β SERIES

dl-9β,16-DIHYDROXY-16-METHYL-3-OXA-13-trans-Δ¹⁹ PROSTADIENOIC ACID

Table II

Treatment of the appropriate cyclopentenones of Table B with thelithiocuprates derived from the vinylstannanes or vinyliodides ofReference Example 3 by the procedure of Reference Example 4 isproductive of the PGE₂ derivatives of Example 1-7 of Table II.

EXAMPLE 1

VINYL TIN

1-trans-tri-n-BUTYLSTANNYL-4-METHYL-4-TRIMETHYLSILOXY-1,7-OCTADIENE

CYCLOPENTENONE

2-(5-CARBOTRIMETHYLSILOXYPENT-2-cis-ENYL)-4-TRIMETHYLSILOXYCYCLOPENT-2-EN-1-ONE

PRODUCT PROSTAGLANDIN OF THE PGE2 SERIES

dl-11α,16-DIHYDROXY-9-OXO-16-METHYL-2-nor-5-cis-13-trans-Δ.sup.19PROSTATRIENOIC ACID

EXAMPLE 2

VINYL TIN

1-trans-tri-n-BUTYLSTANNYL-4-METHYL-4-TRIMETHYLSILOXY-1,7-OCTADIENE

CYCLOPENTENONE

2-(6-CARBOTRIMETHYLSILOXYHEX-2-cis-ENYL)-4-TRIMETHYLSILOXYCYCLOPENT-2-EN-1-ONE

PRODUCT PROSTAGLANDIN OF THE PGE2 SERIES

dl-11α,16-DIHYDROXY-9-OXO-16-METHYL-5-cis-13-trans-Δ¹⁹ PROSTATRIENOICACID

EXAMPLE 3

VINYL TIN

1-trans-tri-n-BUTYLSTANNYL-4-METHYL-4-TRIMETHYLSILOXY-1,7-OCTADIENE

CYCLOPENTENONE

2-(7-CARBOTRIMETHYLSILOXYHEPT-2-cis-ENYL)-4-TRIMETHYLSILOXYCYCLOPENT-2-EN-1-ONE

PRODUCT PROSTAGLANDIN OF THE PGE2 SERIES

dl-11α,16-DIHYDROXY-9-OXO-16-METHYL-2-homo-5-cis-13-trans-Δ.sup.19PROSTATRIENOIC ACID

EXAMPLE 4

VINYL TIN

1-trans-tri-n-BUTYLSTANNYL-4-METHYL-4-TRIMETHYLSILOXY-1,7-OCTADIENE

CYCLOPENTENONE

2-(6-CARBOTRIMETHYLSILOXYHEX-2-cis-ENYL)-4R-TRIMETHYLSILOXYCYCLOPENT-2-EN-1-ONE

PRODUCT PROSTAGLANDIN OF THE PGE2 SERIES

nat-11α,16-DIHYDROXY-9-OXO-16-METHYL-5-cis-13-trans-Δ¹⁹ PROSTATRIENOICACID

EXAMPLE 5

VINYL TIN

1-trans-tri-n-BUTYLSTANNYL-4-METHYL-4-TRIMETHYLSILOXY-1,7-OCTADIENE

CYCLOPENTENONE

2-(5-CARBOETHOXYPENT-2-cis-ENYL)CYCLOPENT-2-EN-1-ONE

PRODUCT PROSTAGLANDIN OF THE 11-DEOXY PGE2 SERIES

dl-16-HYDROXY-9-OXO-16-METHYL-2-nor-5-cis-13-trans-Δ¹⁹ PROSTATRIENOICACID

EXAMPLE 6

VINYL TIN

1-trans-tri-n-BUTYLSTANNYL-4-METHYL-4-TRIMETHYLSILOXY-1,7-OCTADIENE

CYCLOPENTENONE

2-(6-CARBOETHOXYHEX-2-cis-ENYL) CYCLOPENT-2-EN-1-ONE

PRODUCT PROSTAGLANDIN OF THE 11-DEOXY PGE2 SERIES

dl-16-HYDROXY-9-OXO-16-METHYL-5-cis-13-trans-Δ¹⁹ PROSTATRIENOIC ACID

EXAMPLE 7

VINYL TIN

1-trans-tin-n-BUTYLSTANNYL-4-METHYL-4-TRIMETHYLSILOXY-1,7-OCTADIENE

CYCLOPENTENONE

2-(7-CARBOETHOXYHEPT-2-cis-ENYL) CYCLOPENT-2-EN-1-ONE

PRODUCT PROSTAGLANDIN OF THE 11-DEOXY PGE2 SERIES

dl-16-HYDROXY-9-OXO-16-METHYL-2-homo-5-cis-13-trans-Δ¹⁹ PROSTATRIENOICACID

Treatment of the PGE₂ derivatives of Examples 1-7 of Table II withlithium perhydro-9β-boraphenalyl hydride by the procedure of ReferenceExample 6 is productive of the PGF₂ α derivatives of Examples 8-14 ofTable II.

EXAMPLE 8

STARTING PROSTAGLANDIN OF THE PGE SERIES

dl-11α,16-DIHYDROXY-9-OXO-16-METHYL-2-nor-5-cis-13-trans-19PROSTATRIENOIC ACID

PRODUCT PROSTAGLANDIN OF THE PGF₂α SERIES

dl-9α,11α,16-TRIHYDROXY-16-METHYL-2-nor-5-cis-13-trans-Δ.sup.19PROSTATRIENOIC ACID

EXAMPLE 9

STARTING PROSTAGLANDIN OF THE PGE SERIES

dl-11α,16-DIHYDROXY-9-OXO-16-METHYL-5-cis-13-trans-19 PROSTATRIENOICACID

PRODUCT PROSTAGLANDIN OF THE PGF2α SERIES

dl-9α,11α,16-TRIHYDROXY-16-METHYL-5-cis-13-trans-Δ¹⁹ PROSTATRIENOIC ACID

EXAMPLE 10

STARTING PROSTAGLANDIN OF THE PGE SERIES

dl-11α,16-DIHYDROXY-9-OXO-16-METHYL-2-homo-5-cis-13-trans-19PROSTATRIENOIC ACID

PRODUCT PROSTAGLANDIN OF THE PGF2α SERIES

dl-9α,11α,16-TRIHYDROXY-16-METHYL-2-homo-5-cis-13-trans-Δ¹⁹PROSTATRIENOIC ACID

EXAMPLE 11

STARTING PROSTAGLANDIN OF THE PGE SERIES

nat-11α,16-DIHYDROXY-9-OXO-16-METHYL-5-cis-13-trans-19 PROSTATRIENOICACID

PRODUCT PROSTAGLANDIN OF THE PGF2α SERIES

nat-9α,11α,16-TRIHYDROXY-16-METHYL-5-cis-13-trans-Δ¹9 PROSTATRIENOICACID

EXAMPLE 12

STARTING PROSTAGLANDIN OF THE PGE SERIES

dl-16-HYDROXY-9-OXO-16-METHYL-2-nor-5-cis-13-trans-19 PROSTATRIENOICACID

PRODUCT PROSTAGLANDIN OF THE 11-DEOXY PGF2α SERIES

dl-9α,16-DIHYDROXY-16-METHYL-2-nor-5-cis-13-trans-Δ¹⁹ PROSTATRIENOICACID

EXAMPLE 13

STARTING PROSTAGLANDIN OF THE PGE SERIES

dl-16-HYDROXY-9-OXO-16-METHYL-5-cis-13-trans-19 PROSTATRIENOIC ACID

PRODUCT PROSTAGLANDIN OF THE 11-DEOXY PGF2α SERIES

dl-9α,16-DIHYDROXY-16-METHYL-5-cis-13-trans-Δ¹⁹ PROSTATRIENOIC ACID

EXAMPLE 14

STARTING PROSTAGLANDIN OF THE PGE SERIES

dl-16-HYDROXY-9-OXO-16-METHYL-2-homo-5-cis-13-trans-19 PROSTATRIENOICACID

PRODUCT PROSTAGLANDIN OF THE 11-DEOXY PGF2α SERIES

dl-9α,16-DIHYDROXY-16-METHYL-2-homo-5-cis-13-trans-Δ¹⁹ PROSTATRIENOICACID

Treatment of the PGE₂ derivatives of Examples of Table II with sodiumborohydride by the procedure of Reference Example 5 is productive of thePGFα and PGFβ derivatives of Examples 15 to 21 of Table II.

EXAMPLE 15

STARTING PROSTAGLANDIN OF THE PGE SERIES

dl-11α,16-DIHYDROXY-9-OXO-16-METHYL-2-nor-5-cis-13-trans-19PROSTATRIENOIC ACID

PRODUCT PROSTAGLANDIN OF THE PGF2β SERIES

dl-9β,11α,16-TRIHYDROXY-16-METHYL-2-nor-5-cis-13-trans-Δ.sup.19PROSTATRIENOIC ACID

EXAMPLE 16

STARTING PROSTAGLANDIN OF THE PGE SERIES

dl-11α,16-DIHYDROXY-9-OXO-16-METHYL-5-cis-13-trans-19 PROSTATRIENOICACID

PRODUCT PROSTAGLANDIN OF THE PGF2β SERIES

dl-9β,11α,16-TRIHYDROXY-16-METHYL-5-cis-13-trans-Δ¹⁹ PROSTATRIENOIC ACID

EXAMPLE 17

STARTING PROSTAGLANDIN OF THE PGE SERIES

dl-11α,16-DIHYDROXY-9-OXO-16-METHYL-2-homo-5-cis-13-trans-19PROSTATRIENOIC ACID

PRODUCT PROSTAGLANDIN OF THE PGF2β SERIES

dl-9β,11α,16-TRIHYDROXY-16-METHYL-2-homo-5-cis-13-trans-Δ.sup.19PROSTATRIENOIC ACID

EXAMPLE 18

STARTING PROSTAGLANDIN OF THE PGE SERIES

nat-11α,16-DIHYDROXY-9-OXO-16-METHYL-5-cis-13-trans-19 PROSTATRIENOICACID

PRODUCT PROSTAGLANDIN OF THE PGF2β SERIES

nat-9β,11α,16-TRIHYDROXY-16-METHYL-5-cis-13-trans-Δ¹⁹ PROSTATRIENOICACID

EXAMPLE 19

STARTING PROSTAGLANDIN OF THE PGE SERIES

dl-16-HYDROXY-9-OXO-16-METHYL-2-nor-5-cis-13-trans-19 PROSTATRIENOICACID

PRODUCT PROSTAGLANDIN OF THE 11-DEOXY PGF2β SERIES

dl-9β,16-DIHYDROXY-16-METHYL-2-nor-5-cis-13-trans-Δ¹⁹ PROSTATRIENOICACID

EXAMPLE 20

STARTING PROSTAGLANDIN OF THE PGE SERIES

dl-16-HYDROXY-9-OXO-16-METHYL-5-cis-13-trans-19 PROSTATRIENOIC ACID

PRODUCT PROSTAGLANDIN OF THE 11-DEOXY PGF2β SERIES

dl-9β,16-DIHYDROXY-16-METHYL-5-cis-13-trans-Δ¹⁹ PROSTATRIENOIC ACID

EXAMPLE 21

STARTING PROSTAGLANDIN OF THE PGE SERIES

dl-16-HYDROXY-9-OXO-16-METHYL-2-homo-5-cis-13-trans-19 PROSTATRIENOICACID

PRODUCT PROSTAGLANDIN OF THE 11-DEOXY PGF2β SERIES

dl-9β,16-DIHYDROXY-16-METHYL-2-homo-5-cis-13-trans-Δ¹⁹ PROSTATRIENOICACID

While specific embodiments of this invention have been described withparticularity herein, it will be understood that the invention embracesall changes and modifications of the particular compounds chosen forpurposes of illustration herein which do not depart from the spirit andscope of the invention.

I claim:
 1. An optically active compound of the formula: ##STR16##wherein Y is ##STR17## X is ##STR18## R₁ is selected from the groupconsisting of hydrogen and hydroxyl; R₂ is selected from the groupconsisting of hydrogen and C₁ C₆ alkyl;R₃ is methyl; Z is selected fromthe group consisting of a divalent moiety of the formulae: --(CH₂)_(n)--, --(CH₂)_(m) OCH₂ -- and --(CH₂)_(m) SCH₂ -- wherein n is 5 to 7,and, m is 3 to 5 and the racemic mixture thereof; and when R₁ ishydrogen, the pharmaceutically acceptable salts thereof.
 2. A compoundaccording to claim 1 wherein Z is --(CH₂)₆ --.
 3. The racemic compoundsaccording to claim 2,11α,16α/β-dihydroxy-9-oxo-16-methyl-13-trans-Δ.sup.19 -prostadienoicacid, the individual 16α- and 16β-hydroxy racemates, and the methylesters thereof.
 4. The optically active compounds according to claim 2,nat. 11α,16α/β-dihydroxy-9-oxo-16-methyl-13-trans-Δ.sup.19-prostadienoic acid, the indibidual 16α- and 16β-hydroxy isomers and themethyl esters thereof.
 5. The racemic compounds according to claim 3,11α,16β-dihydroxy-9-oxo-16-methyl-13-trans-Δ¹⁹ -prostenoic acid, methylester.